WO2022249136A1 - Complément alimentaire - Google Patents

Complément alimentaire Download PDF

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Publication number
WO2022249136A1
WO2022249136A1 PCT/IB2022/054985 IB2022054985W WO2022249136A1 WO 2022249136 A1 WO2022249136 A1 WO 2022249136A1 IB 2022054985 W IB2022054985 W IB 2022054985W WO 2022249136 A1 WO2022249136 A1 WO 2022249136A1
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WIPO (PCT)
Prior art keywords
mfgm
infant
components
months
child
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PCT/IB2022/054985
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English (en)
Inventor
Sophie Yvette Fabienne Christine GALLIER
Christopher Paul Mcjarrow
Angela Marie Rowan
Bing Wang
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Fonterra Co-Operative Group Limited
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Application filed by Fonterra Co-Operative Group Limited filed Critical Fonterra Co-Operative Group Limited
Priority to AU2022282664A priority Critical patent/AU2022282664A1/en
Priority to EP22810773.6A priority patent/EP4346449A1/fr
Priority to CN202280052380.6A priority patent/CN117794394A/zh
Publication of WO2022249136A1 publication Critical patent/WO2022249136A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to the use of milk fat globule membrane (MFGM) or components thereof for improving developmental outcomes in an infant or child subject, in particular for improving social-emotional behaviour and/or improving memory.
  • MFGM milk fat globule membrane
  • BACKGROUND The first 1000 days of life, from conception to the end of two years postpartum, is a critical phase during which the foundations of a child’s development are laid. If a child’s body and brain develop well, then their life chances are improved. Suboptimal nutrition during this period of life affects brain development, ranging from neuroanatomy, neurochemistry, neurophysiology, and neuropsychology to long-lasting influences on cognitive events well into adulthood (1) .
  • the milk fat globule membrane (MFGM) (6; 7) of mammalian milks comprises three polar lipid layers consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, plasmalogens, gangliosides, cholesterol, protein, and membrane-specific glycoproteins.
  • Gangliosides are sialic-acid-containing glycosphingolipids in milk almost exclusively associated with the MFGM (8) .
  • Sphingolipids and cholesterol are essential components of myelin (12) , which is an electrical insulator and enhances cell signal transmission and cellular communication in the brain neural network (13) .
  • myelin (12) is an electrical insulator and enhances cell signal transmission and cellular communication in the brain neural network (13) .
  • These lipids also contribute to gut maturation and protection against respiratory and gastrointestinal infections in infancy and childhood (6; 14) .
  • Human milk is the gold standard for feeding infants. However, when breastfeeding is not possible, infant and follow-on formulas are the only suitable alternative.
  • Maternal formulas, infant formulas, follow-on formulas, growing-up formulas, dietetic products and other dairy containing compositions are typically produced using non-human milk.
  • the nutritional composition of human milk differs in some respects to that of non-human milk.
  • non-human whole milk such as cow, goat or sheep milk
  • milk fat is typically replaced with vegetable oils during the manufacture of pediatric formulas; the formulas are therefore depleted of the milk fat globule membrane (MFGM) and its components.
  • Vegetable oils which lack the bioactive lipid components of MFGM, have been used as the only source of lipids matching the fatty acid profile of human milk (7) .
  • the recent commercial availability of bovine MFGM has increased its availability as a functional ingredient in infant formula (15) .
  • Animal studies have shown that MFGM may alter brain lipid composition and functional and cognitive development, possibly through early up- regulation of the genes involved in brain function (6; 16; 17; 18) .
  • infant formula supplemented with phospholipids and gangliosides from the MFGM and with higher arachidonic acid improved cognitive development in healthy infants aged 0–6 months (21) .
  • the responses in previous studies (19; 20; 21) may not be due entirely to MFGM, as experimental and control formulae varied in more parameters than just their MFGM concentration. It would be highly desirable to reduce any gaps in the cognitive development of formula- fed babies and children compared to breast-fed babies and children. It is therefore an object of the present invention to provide means for reducing any gaps in specific areas of cognitive development in formula-fed babies compared to breast-fed babies.
  • a first aspect of the invention relates to milk fat globule membrane (MFGM) and/or one or more of its components for improving social-emotional behaviour and/or improving memory in an infant or child subject.
  • a further aspect of the invention provides a method for improving social-emotional behaviour and/or improving memory in an infant or child subject, comprising administering MFGM and/or one or more of its components in a suitable form to a mother during gestation and/or postpartum during lactation, and/or to the infant or child subject (in need thereof).
  • the invention in another aspect, relates to a method of using MFGM and/or one or more of its components for improving social-emotional behaviour and/or improving memory, the method comprising administering MFGM and/or one or more of its components in a suitable form to a pregnant or lactating mother and optionally informing the mother that administered compound will subsequently maintain or improve social-emotional behaviour and/or maintain or improve memory in her child in the weeks, months and years following birth.
  • the invention also provides MFGM and/or one or more components thereof for use in therapy. Also provided are MFGM and/or one or more components thereof in the treatment or prevention of any of the following: attention deficit hyperactivity disorder (ADHD), arthritis, migraines and repeated headaches in an infant or child subject.
  • ADHD attention deficit hyperactivity disorder
  • arthritis migraines and repeated headaches in an infant or child subject.
  • the treatment or prevention comprises administering an effective amount of MFGM and/or one or more of its components to an infant or child subject in need thereof. Also provided by the invention is the use of MFGM and/or one or more of its components in the manufacture of a formulation for improving social-emotional behaviour and/or improving memory in an infant or child subject. Also provided by the invention is the use of MFGM and/or one or more of its components in the manufacture of a formulation or a medicament for the treatment of one or more of: attention deficit hyperactivity disorder (ADHD), arthritis, migraines and repeated headaches in an infant or child subject.
  • ADHD attention deficit hyperactivity disorder
  • the invention also provides a food ingredient, food product or dietary supplement comprising, consisting of or essentially consisting of MFGM and/or one or more of its components for use in improving social-emotional behaviour and/or improving memory in an infant or child subject.
  • MFGM milk fat globule membrane
  • a first aspect of the invention relates to milk fat globule membrane (MFGM) and/or one or more of its components for improving social-emotional behaviour and/or improving memory in an infant or child subject.
  • the MFGM and/or one or more of its components are for administration or are administered in a suitable form to a mother during gestation and/or lactation, or to an infant or child subject (in need thereof).
  • the milk fat globule membrane (MFGM) is a well-known component of milk. It is composed primarily of lipids and proteins that surround milk fat globules secreted from the milk producing cells of humans and other mammals.
  • the MFGM has a phospholipid trilayer structure that contains other polar lipids (such as gangliosides (GA) and cerebrosides), MFGM proteins and cholesterol.
  • the predominant MFGM phospholipids in human and bovine milk are phosphatidylcholine (PC), sphingomyelin (SM) and phosphatidylethanolamine (PE) with smaller amounts of phosphatidylserine (PS) and phosphatidylinositol (PI). Cholesterol and sphingomyelin form lipid rafts.
  • the innermost layer of the MFGM is derived from the endoplasmic reticulum and the external bilayer of the MFGM derives from the apical plasma membrane of the mammary cell. Glycosylated lipids and proteins form the glycocalyx sticking out into the aqueous phase.
  • MFGM a complex mixture of various proteins, lipids and other components, as described above, accurately quantifying MFGM in its totality is currently not possible.
  • the presence and amount of MFGM in a product is therefore determined by measuring one or more of its major components, such as phospholipids, gangliosides and MFGM proteins. Individual phospholipid species can be measured, for example, by HPLC-ELSD/CAD, 31 P NMR, and HPLC-MS.
  • Quantitative approaches for MFGM proteins include western blotting and HPLC-MS, and for glycosphingolipids such as GA, thin layer chromatography and HPLC-MS (see Gallier et al., 2018, Agro Food Industry Hi Tech, Vol. 29(5)).
  • MFGM components are taken to mean any one or more components that can be found in MFGM, such as one or more phospholipids, one or more sphingolipids, one or more sphingomyelins or derivatives thereof, one or more ceramides, one or more cerebrosides, one or more gangliosides, one or more MFGM proteins, or any combination thereof, which components are useful in improving social-emotional behaviour and improving memory in an infant or child subject.
  • the one or more phospholipids may be selected from: phosphatidylcholine (PC), sphingomyelin (SM) and phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI), or any combination thereof.
  • the one or more MFGM proteins may be selected from: Xanthine Oxidase, Butryophilin, Fatty acid binding protein, PAS6/7, adipophilin, Mucin 1, CD36, Mucin 15 and others, or any combination thereof.
  • the one or more gangliosides may be selected from: GM1, GM2, GM3, GM4, GD1, GD2, GD3, GT1, GT2, GT3, GQl, and GPl, and any one or more of the "a", "b", or “c” derivatives where they exist, and any combinations thereof.
  • administering MFGM and/or its components to an infant or child subject, for example, through a suitable composition or formulation, as described herein raised serum ganglioside levels to levels similar to those seen in breast-fed subjects.
  • MFGM-supplemented subjects showed increases in serum ganglioside levels or concentrations of GM3 (monosialodihexosylganglioside), GD3 (disialoganglioside 3), GM1 (monosialotetrahexosylganglioside), GD1a (disialoganglioside 1a) and GD1b (disialoganglioside 1b), as well as in the sum of these gangliosides.
  • GM3 monosialodihexosylganglioside
  • GD3 disialoganglioside 3
  • GM1 monosialotetrahexosylganglioside
  • GD1a disialoganglioside 1a
  • GD1b disialoganglioside 1b
  • the technical effect of the present invention of improving social-emotional behaviour and/or improving memory, particularly short term memory and/or concentration, in an infant or child subject may also therefore advantageously be achieved through the administration to a subject of components of MFGM, particularly gangliosides, such as any one or more of GM1: monosialotetrahexosylganglioside; GM2: monosialoganglioside 2; GM3: monosialodihexosylganglioside; GD1a: disialoganglioside 1a; GD1b: disialoganglioside 1b; GD3: disialoganglioside 3.
  • GM1 monosialotetrahexosylganglioside
  • GM2 monosialoganglioside 2
  • GM3 monosialodihexosylganglioside
  • GD1a disialoganglioside 1a
  • the ganglioside is any one or more of: GM3, GD3, GM1, GD1a and GD1b or similar, and any combinations thereof.
  • the ganglioside(s) may be dietary ganglioside(s).
  • Gangliosides are a group of sialic-acid-containing glycosphingolipids and may be found in animal tissues and fluids, such as blood, brain tissue and milk. Gangliosides may be extracted from milk or from other animal sources, such as beef, chicken, pork, and fish and marine species, such as sea urchin. Gangliosides may also be produced synthetically or semi-synthetically.
  • Gangliosides may be measured using known techniques, such as by measuring Lipid Bound Sialic Acid (LBSA) or individual species quantified by Thin Layer Chromatography (TLC), High Performance Liquid Chromatography with UV detection (HPLC-UV), or by liquid chromatography linked to mass spectrometry (LC-MS).
  • LBSA Lipid Bound Sialic Acid
  • TLC Thin Layer Chromatography
  • HPLC-UV High Performance Liquid Chromatography with UV detection
  • LC-MS liquid chromatography linked to mass spectrometry
  • MFGM or components thereof may suitably be derived from any mammalian milk, such as cow, buffalo, goat, sheep, or human milk.
  • MFGM or components thereof are bovine in origin.
  • components of MFGM are derived from any mammalian milk, such as cow, buffalo, goat, sheep, or human milk.
  • MFGM and/or components thereof may be extracted from milk or other dairy sources, particularly any high fat milk fraction, for example: cream, butter, buttermilk, butter serum, beta serum and whey protein concentrates enriched in MFGM.
  • Advances in dairy processing have made possible the MFGM enrichment of dairy streams, which has given the ability to match the human milk fat globule membrane composition and structure in formulations.
  • MFGM and/or components thereof are produced through enrichment of dairy streams to produce food products or ingredients enriched in MFGM and/or components thereof.
  • Milk fat globule membrane material may be isolated according to the acidification method of Kanno & Dong-Hyun, 1990, and further fractionated into lipid and protein fractions by the addition of methanol, as described by Kanno et al., 1975.
  • a phospholipid extract may be isolated by extracting the lipid mixture with acetone according to the procedure of Purthi et al., 1970.
  • Lipid residue may be further enriched in milk fat globule membrane lipids by the selective extraction of non-polar lipids with pentane.
  • MFGM and MFGM components are also commercially available under, for example, the product names SureStartTM (such as SureStartTMMFGM Lipid 100 and SureStartTMMFGM Lipid 70) and LacprodanTM.
  • Bayley-III Cognitive, Language, Motor, Social-emotional, and Adaptive. Cognitive, Language and Motor development are assessed with the child, while Social-Emotional and Adaptive development are assessed through questionnaire to the parent or caregiver. Cognitive development can be considered the assessment of the way the infant or child’s thinking develops, while social-emotional development is how the individual interacts with others and learn to understand the emotions of others.
  • the Bayley’s III Cognitive Scale involves up to 91 items that assess sensorimotor development, exploration and manipulation, object relatedness, concept formation and memory at different ages.
  • Memory includes both long term and short term, with both memory activities being a subset of the cognitive scale within the Bayley’s III.
  • the Social-Emotional scale assesses self-regulation and interest in the world, communication of needs, engagement with others and establishment of relationships, use of emotions in an interactive, purposeful way, and the use of emotional signals/gestures for problem solving.
  • An improvement in “social-emotional” behaviour may be measured using the Bayley Scales of Infant and Toddler Development, Third Edition (“Bayley-III”), see Chapter 5 “The Bayley-III Social-Emotional Scale”.
  • An improvement in social-emotional behaviour may be manifested as an improvement in the score at any one of more of stages 1, 2, 3, 4a, 4b, 5a, 5b or 6, as shown in the table below.
  • An improvement in social-emotional behaviour may be relative to non-MFGM supplemented subjects. An improvement may also be registered when a smaller difference is seen between the scores of an MFGM-supplemented subject and breast-fed subjects compared to the difference between the scores of non-MFGM supplemented subjects and breast-fed subjects.
  • Reference herein to breast-fed subjects refers to infants who are breast-fed at least 90% of the time for the first four to six months of life.
  • Reference herein to non-breast-fed subjects refers to subjects who receive formula-milk, whether supplemented or not, at least 90% of the time for the first twelve months of life.
  • An “improvement” in social-emotional behaviour also encompasses the maintenance or reduction or prevention of decline in social-emotional behaviour for the subject in question.
  • An improvement in memory may also be determined by measuring changes in the hippocampus, amygdala or prefrontal cortex, as opposed to changes in the frontal lobe, which is responsible for initiating and coordinating motor movements, higher cognitive skills, such as problem solving, thinking, planning, and organising, and for many aspects of personality and emotional makeup.
  • the improvement in memory is preferably an improvement in short-term memory and/or an improvement in attention.
  • the assessment of memory, including short-term memory and/or attention, and what constitutes an improvement will vary depending on the developmental stage / age of the subject.
  • An improvement in memory, including short-term memory and/or attention may be relative to non-MFGM supplemented subjects of the same age.
  • An improvement may also be registered when a smaller difference is seen between the scores or results of an MFGM-supplemented subject and breast-fed subjects compared to the difference between the scores or results of non-MFGM supplemented subjects and breast-fed subjects of the same age.
  • breast-fed subjects refers to infants who are breast-fed at least 90% of the time for the first four to six months of life.
  • non-breast-fed subjects i.e. to those receiving formula, whether or not supplemented with MFGM, refers to subjects who receive formula-milk at least 90% of the time for the first twelve months of life.
  • (short-term) memory and/or attention is increased by at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30% or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% compared to non-MFGM supplemented subjects.
  • An “improvement” in memory also encompasses maintenance or the reduction or prevention of decline in memory in the subject in question.
  • the MFGM and/or one or more components thereof may be comprised in a food product or may be used as an ingredient or provided as a dietary supplement.
  • the invention therefore provides a food product, ingredient and dietary supplement comprising, consisting of or essentially consisting of MFGM and/or one or more of its components for use in improving social-emotional behaviour and/or improving memory in an infant or child subject.
  • the MFGM and/or components thereof may be also comprised in a composition or formulation.
  • MFGM and/or components thereof may be provided in the form of MFGM-enriched products and ingredients or may be provided as an enriching agent.
  • MFGM or components thereof may be formulated as a food, drink, food additive or ingredient, drink additive or ingredient, dietary supplement, nutritional product, medical food, enteral or parenteral feeding product, meal replacement, or pharmaceutical.
  • the food product may be an infant, follow-on, growing up, or maternal formula.
  • infant formula as referred to herein is taken to mean a composition for infants aged between 0 days and 6 months old and a "follow-on formula” refers to a composition fornfants aged 6 months to 1 year.
  • growing up formula refers to compositions directed to infants and children aged 1 year upwards. Growing-up formulancludes growing-up milk powders or GUMPs.
  • compositions can vary from child to child depending on thendividual's development.
  • term “maternal formula” as used herein refers to a composition to be taken by pregnant or lactating women.
  • the food product can also be a dietetic product, which refers to a product specially processed or formulated to satisfy particular dietary requirements which exist because of a particular physical or physiological condition and/or specific diseases and disorders and which are presented as such.
  • the aforementioned products may be in liquid form as concentrates or ready-to- drink liquids or provided as powder concentrates.
  • the MFGM-containing food product may also be any other dairy product, such as yoghurt, cheese, cream, buttermilk, beta serum, butter serum, high fat whey protein concentrate, high fat milk protein concentrate, high fat whey protein isolate, high fat milk protein isolate or fractions thereof, or MFGM or one or more components thereof may be derived from any of the aforementioned products.
  • the products may themselves bengredients for further use in other areas of the food and drinks industry.
  • the products may be MFGM-enriched products and ingredients, produced through the enrichment of dairy streams.
  • Beta-serum refers to an aqueous dairy ingredient separated from dairy streams containing greater than 60% w/w fat that have been through phase inversion from an oil-in-water to a water-in-oil emulsion, as described below.
  • Cream is the preferred starting material for the production of beta-serum.
  • beta-serum is produced during the production of anhydrous milk fat (or AMF) from cream.
  • Butter serum is the aqueous phase produced by the melting of butter to produce butter oil.
  • the beta serum or butter serum is dried; preferably dried beta-serum or butter serum is a powder.
  • the MFGM-containing food product may also be a non-dairy product such as baby food, fruit juices, (baby) rice, rusks, puree, or porridge.
  • the MFGM and/or components thereof may be used as an ingredient, such as a fortifying agent, e.g. human milk fortifier.
  • the MFGM and/or components thereof may be provided as a dietary supplement, such as in the form of oil drops, gummy, tablet, a caplet, a pill, a hard or soft capsule, or lozenge.
  • the supplement may be in the form of a sachet, dispensable powder, granules, suspension, an elixir, a liquid, or any other form that can be added to food or drink, including for example water, milk or fruit juice.
  • the food products, ingredients or dietary supplements may further comprise probiotics and/or prebiotics.
  • Suitable prebiotics may include human milk oligosaccharides, galacto- oligosaccharides, fructo-oligosaccharides and inulin.
  • Suitable probiotics may include bifidobacteria, lactobacilli, Bifidobacterium animalis subsp.
  • a further aspect of the invention provides a method for improving social-emotional behaviour and/or improving memory in an infant or child subject, comprising administering a formulation comprising MFGM and/or one or more of its components to a mother during gestation or lactation or to the infant or child subject (in need thereof).
  • the method or the improvement may be non-therapeutic.
  • the formulation is preferably administered orally.
  • oral administration includes oral, buccal, enteral and intra-gastric administration.
  • the formulation may comprise a suitable carrier, diluent or excipient, or combination thereof, to allow the formulation to be effectively administered to a subject without reducing the activity of the MFGM and/or one or more of its components.
  • the "subject" of the invention is an infant or child subject and may be an animal, preferably a mammal, more preferably a mammalian companion animal or human. Preferred companion animals include cats, dogs and horses.
  • the subject of the invention is preferably a human.
  • the subject of the invention is foetus, infant or child, the subject having improved social- emotional behaviour and/or improved memory following administration of MFGM and/or one or more of its components to the subject itself and/or to its mother during gestation and/or postpartum during lactation.
  • the subject of the invention may be an otherwise “healthy” individual, for example, as determined by the Apgar scoring system (The American College of Obstetricians and Gynecologists, No. 644, Oct 2015) in the case of a newborn, or through the use of standard growth curves, such as WHO Child Growth Standards (Acta Paediatrica, 2006, Suppl 450: 76-85) for older subjects.
  • the WHO Child Growth Standards may be used to convert weight, length, and head circumference into weight-for-age, length-for-age, and head-circumference-for-age Z-scores (26; 27) .
  • the subject of the invention may suitably be “full term”, meaning a baby born after the end of the 37th week of gestation.
  • a “healthy” subject does not include low birth weight infants, very low birth weight infants, and premature infants, “premature” being a baby born before the end of the 37th week of gestation. Although, the aforementioned does not apply once the previously premature or low birth weight subjects enter into the healthy range.
  • infant or child as defined herein is taken to mean a child of any age from birth onwards, until pre-pubescence, anytime between the ages of ten and fourteen.
  • the infant or child subject may be between 0-3 months, 4-5 months, 6-9 months, 10-14 months, 15-18 months, 19-24 months, 25-30 months, 31-42 months.
  • the infant or child subject may be up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine or thirty days in age.
  • the infant or child subject may be up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, or up to twenty-four months of age.
  • the infant or child subject may be up to one year in age, or up to two years of age, or up to three years of age, or up to four years of age, or up to five years of age, or up to six years of age, or up to seven years of age, or up to eight years of age, or up to nine years of age, or up to ten years of age, or up to eleven years of age or up to twelve years of age, or up to thirteen years of age or up to fourteen years of age or of any age prior to the onset of puberty.
  • the formulation is administered to the expectant mother.
  • the expectant mother may suitably be up to one, two, three, four, five, six, seven, eight or nine months pregnant.
  • the formulation of the invention may also be administered postpartum to a lactating mother, whereby the formulation is delivered to the baby or infant through breastfeeding and/or through supplementation of expressed milk. Where the formulation is administered to the expectant mother or postpartum, the resulting improvement is seen in the infant or child in the weeks, months and years after the birth.
  • the improvement in social-emotional behaviour and/or in memory may be seen from birth onwards until the child is up to one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, or up to twelve years of age, and suitably where the child is not fed an MFGM-supplemented formula nor substantially breast-fed.
  • the resulting improvement in social-emotional behaviour and/or memory may be seen in the days, weeks or months following administration of MFGM and/or one or more of its components to the subject.
  • the improvement in social-emotional behaviour and/or memory is relative to non-MFGM supplemented subjects of the same age.
  • An improvement may also be registered when the differences in social- emotional behaviour and/or memory in MFGM-supplemented subjects and breast-fed subjects is reduced compared to the differences (or gap) between non-MFGM supplemented subjects and breast-fed subjects of the same age.
  • An “improvement” in social-emotional behaviour and/or memory may also be realised where there is maintenance or a reduction or prevention in decline in social-emotional behaviour and/or memory in the subject in question.
  • an infant or child subject may be identified as being in need of treatment due to, for example, the subject having an Apgar score or growth rate falling outside of the normal healthy range for their age, or where the subject is identified as having low or declining social-emotional behaviour or low or declining memory (particularly low short term memory or attention).
  • a subject may be identified as being in need of treatment by a suitable health professional and/or through appropriate testing.
  • identifying refers to detecting or selecting a subject from a population of potential subjects, for example, to establish that a particular subject possesses certain properties or characteristics. “Identifying” may include, for example, self-identification, self-diagnosis, and diagnosis by a suitable health professional.
  • infant or child subjects deficient in MFGM and /or components thereof may be at risk of developing, or may suffer from, any of the following: attention deficit hyperactivity disorder (ADHD), arthritis, migraines and repeated headaches. Therefore, a further aspect of the invention provides MFGM and/or one or more components thereof for use in therapy. A further aspect of the invention also provides MFGM and/or one or more components thereof for use in the treatment or prevention of any of the following: attention deficit hyperactivity disorder (ADHD), arthritis, migraines and repeated headaches in an infant or child subject.
  • the treatment or prevention comprises administering an effective amount of MFGM and/or components thereof to a subject in need thereof.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the subject will develop the disease or condition.
  • MFGM and/or components thereof may also be provided to a subject to maintain or to prevent or reduce the decline in social-emotional behaviour and/or memory (particularly any decline in short term memory and/or attention).
  • a further aspect of the invention relates to a method of using MFGM and/or one or more of its components for improving social-emotional behaviour and/or improving memory, the method comprising providing a pregnant mother with MFGM and/or one or more of its components (in a formulation or other suitable form) and optionally informing the mother that the formulation will subsequently maintain or improve social-emotional behaviour and/or improve memory (particularly short term memory and/or attention) in her child once born.
  • the improvement in social-emotional behaviour and/or in memory may be seen from birth onwards until the child is up to one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, or up to twelve years of age, and suitably where the child is not fed an MFGM-supplemented formula nor substantially breast-fed.
  • an effective amount of the formulation is administered to the mother during gestation and/or lactation, or to the infant or child subject, an effective amount being the amount required to confer an improvement in social-emotional behaviour and/or memory in an infant or child subject.
  • the interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich, et al. (1966). Body surface area can be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537. Effective doses also vary, as recognised by those skilled in the art, dependent on route of administration, carrier usage, and the like.
  • MFGM and/or components thereof may be administered to a subject on an hourly basis, e.g., every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three hours, or any interval in between, or on a daily basis, every two days, every three days, every four days, every five days, every six days, every week, every eight days, every nine days, every ten days, every two weeks, every month, or more or less frequently, as needed to achieve the desired effect.
  • Formulations and compositions suitable for use in the invention may comprise at least about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or at least about 1% gangliosides w/w on a dry weight basis.
  • formulations and compositions useful in the invention may comprises at least about 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 2000mg, 3000mg, 4000mg, 5000mg, 6000mg, 7000mg, 8000mg, 9000mg, or at least about 10,000 mg or more
  • infant or follow-on formulations useful in the invention comprise in the range of between about 15–65mg (such as about 18-65mg) gangliosides per 100g dry weight, or 2-25mg (such as about 5-20mg, or 4-15mg, or 3-17mg) gangliosides per 100g dry weight in the case of growing up milk or maternal milk.
  • the formulation when administered during pregnancy or lactation is formulated to provide at least about 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, or at least about 100mg gangliosides per 100g dry weight, such as at least about 5-50mg, 10-50mg, optionally at least about 7.5-10mg gangliosides per 100g dry weight, per day to the mother, and useful ranges may be chosen between any of these values (for example, about 1 to about 100mg gangliosides per 100g dry weight per day to the mother, or about 2 to about 60mg gangliosides per 100g dry weight per day to the mother,
  • the formulations of the invention do not comprise lactoferrin. In certain embodiments, the formulations of the invention do not comprise arachidonic acid.
  • the technical effects of the present invention appear to be entirely attributable to MFGM alone, or to components of MFGM.
  • the formulations of the invention advantageously provide improvements in social- emotional behaviour and/or memory in infant or child subjects compared with subjects provided with the same formulation but without MFGM supplementation. According to the invention, improvements seen in social-emotional behaviour and/or memory in infant or child subjects are solely due to the provision of MFGM, or MFGM polar lipid components over baseline.
  • a formulation (infant, follow-on, growing up or maternal) useful herein may comprise on a solids basis: (a) 80—99.9% w/w of a milk powder selected from whole milk powder, skim milk powder, milk protein concentrate (MPC), milk protein isolate (MPI); and whey protein such as a WPC, WPI or demineralised whey; (b) 0—30% w/w of a lipid source such as milk fat or one or more vegetable oil; (c) 0—25% w/w sugars or carbohydrate ingredient; (d) 0.1—0.5% w/w vitamin and mineral mix; (e) 0—5% w/w flavour ingredients, and (f) 1—20% w/w MFGM or one or more components thereof.
  • a milk powder selected from whole milk powder, skim milk powder, milk protein concentrate (MPC), milk protein isolate (MPI); and whey protein such as a WPC, WPI or demineralised whey
  • Part (f) above may also be 1-50% w/w MFGM or one or more components thereof, with parts (a) to (e) adjusted accordingly.
  • the MFGM when administered in an infant formula or follow-on formula, may comprise, consist of, or essentially consist of each of the following components per 100g dry weight, or of any one or more of components (a) to (g) per 100g dry weight: (a) Phospholipids: 400-700 mg (b) Phosphatidylcholine: 100-200 mg (c) Phosphatidylethanolamine: 100-200 mg (d) Phosphatidylinositol: 30-65 mg (e) Phosphatidylserine: 35-95 mg (f) Sphingomyelin: 90-200 mg (g) Gangliosides: 18-65 mg When administered in a growing up milk, the MFGM may comprise, consist of or essentially consist of each of the following components per 100g dry weight, or of any one or more
  • the respective quantities of elements (a) to (g) would of course vary for a smaller or greater serving size or according to the number of servings.
  • Phospholipids 225-450 mg
  • Phosphatidylcholine 55-120 mg
  • Phosphatidylethanolamine 50-120 mg
  • Phosphatidylinositol 15-40 mg
  • Phosphatidylserine 20-40 mg
  • Sphingomyelin 50-115 mg
  • Gangliosides 4-15 mg
  • the growing up milk may, for example, be provided in two daily servings of 28g to give a daily total of 56g/day, or in three daily servings of 28g to give a daily total of 84g/day delivering the following amounts.
  • the respective quantities of elements (a) to (g) would of course vary for a smaller or greater serving size or according to the number of servings.
  • Phospholipids 165-500 mg
  • Phosphatidylcholine 40-135 mg
  • Phosphatidylethanolamine 40-135 mg
  • Phosphatidylinositol 10-40 mg
  • Phosphatidylserine 15-60 mg
  • Sphingomyelin 40-126 mg
  • Gangliosides 3-17 mg
  • the feeding requirements of babies will vary greatly as they grow.
  • the table below shows the typical recommended feeds per day according to age and the respective quantities of MFGM components.
  • formulations may also comprise 0.1 to 4% w/w, preferably 2 to 4% w/w on a dry weight basis, of one or more of a vitamin premix, a mineral premix, lecithin, one or more antioxidants, one or more stabilisers, or one or more nucleotides, or a combination of any two or more thereof.
  • the formulations may also comprise flavorings. Amounts expressed herein are by weight of the composition on a dry weight basis unless specifically stated otherwise. The skilled artisan will appreciate that the term "dry weight basis" means that an ingredient's concentration or percentage in a composition is measured or determined after any free moisture in the composition has been removed.
  • these formulations may be formulated to provide from about 2700 to about 3000 kJ/L.
  • the formulation may be a liquid (concentrate or ready-to-drink) or powdered maternal formula, infant formula, follow-on formula, growing-up formula or dietetic product.
  • the formulation may comprise, on a dry weight basis, at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 15, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.58, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 or 99.5% total lipid, and useful ranges may be selected between any of these values (for example, about 5 to about 95%, about 10 to about 95%, about 15 to about 95%, about 20 to about 95%, about 25 to about 95%, about 30 to about 95%, about 35 to about 95%, about 40 to about 95%, about 45 to about 95%, about 50 to about 95%, about 5 to about 99%, about 10 to about 99%, about 15 to about 99%, about 20 to about 99%, about 25 to about 99%, about 30 to about 99%, about 35 to about 99%, about 40 to
  • the formulation may comprise, on a dry weight basis, at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 15, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 or 99.5% by weight phospholipid, and useful ranges may be selected between any of these values (for example, about 5 to about 95%, about 10 to about 95%, about 15 to about 95%, about 20 to about 95%, about 25 to about 95%, about 30 to about 95%, about 35 to about 95%, about 40 to about 95%, about 45 to about 95%, about 50 to about 95%, about 5 to about 99%, about 10 to about 99%, about 15 to about 99%, about 20 to about 99%, about 25 to about 99%, about 30 to about 99%, about 35 to about about 99%,
  • the formulation may comprise, on a dry weight basis, at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30% by dry weight of one or more phospholipids selected independently from phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, and phosphatidylinositol, and useful ranges may be selected between any of these values (for example, about 0.1 to about 30%, about 0.5 to about 30%, about 1 to about 30%, about 2 to about 30%, about 3 to about 30%, about 4 to about 30%, about 5 to about 30%, about 10 to about 30%, about 15 to about 30%, about 20 to about 30%, about 0.1 to about 5%, about 0.5 to about 5%, about 1 to about 5%, about 2 to about 5%, about 3 to about 5%, about 0.1 to about 10%, about 0.5
  • the formulation may comprise, on a dry weight basis, at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 15, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99.5% by dry weight ganglioside, and useful ranges may be selected between any of these values (for example, about 5 to about 95%, about 10 to about 95%, about 15 to about 95%, about 20 to about 95%, about 25 to about 95%, about 30 to about 95%, about 35 to about 95%, about 40 to about 95%, about 45 to about 95%, about 50 to about 95%, about 10 to about 70%, about 15 to about 70%, about 20 to about 70%, about 25 to about 70%, about 30 to about 70%, about 35 to about 95%, about 40 to about 95%, about 45 to about 9
  • the formulation may comprise one or more gangliosides selected from GM1, GM2, GM3, GM4, GDI, GD2, GD3, GT1, GT2, GT3, GQl, and GPl, and any one or more of the "a", "b", or "c” derivatives where they exist, and any combination thereof.
  • the gangliosides in the formulation comprise, consist of or essentially consist of the following: GM3, GD3, GM1, GD1a, GD1b, or any combination thereof.
  • the formulation may comprise, on a dry weight basis, at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% by dry weight of one or more gangliosides, optionally selected independently from GM3, GD3, GM1, GD1a and GD1b, and useful ranges may be selected between any of these values (for example, about 0.1 to about 50%, about 0.5 to about 50%, about 1 to about 50%, about 2 to about 50%, about 3 to about 50%, about 4 to about 50%, about 5 to about 50%, about 10 to about 50%, about 15 to about 50%, about
  • the formulation may comprise about 5% to about 99% by dry weight total lipid (such as 15% to about 99%), about 1% to about 80% by dry weight phospholipid, about 1% to about 25% by dry weight phosphatidylcholine, about 0.1% to about 15% by dry weight phosphatidylinositol, about 0.1% to about 15% by dry weight phosphatidylserine, about 1% to about 30% by dry weight phosphatidylethanolamine, about 0.5% to about 25% by dry weight sphingomyelin, and about 0.1 to about 10% by dry weight ganglioside.
  • the formulation comprises one or more gangliosides, comprises about 1% to about 60% by dry weight lactose, about 1% to about 15 % by dry weight lactose or about 50% to about 65% by dry weight lactose.
  • a further aspect of the invention provides the use of MFGM and/or one or more of its components in the manufacture of a formulation for improving social-emotional behaviour and/or improving memory in an infant or child subject. Also provided in a further aspect of the invention is the use of MFGM and/or one or more of its components in the manufacture of a formulation or a medicament for the treatment of one or more of: attention deficit hyperactivity disorder (ADHD), arthritis, migraines and repeated headaches in an infant or child subject.
  • ADHD attention deficit hyperactivity disorder
  • the formulation may comprise, consist essentially of, or consist of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, or 100% by dry weight of fresh, recombined or powdered whole milk or a milk derivative and useful ranges may be selected between any of these foregoing values (for example, from about 0.1 to about 50%, from about 0.2 to about 50%, from about 0.5 to about 50%, from about 1 to about 50%, from about 5 to about 50%, from about 10 to about 50%, from about 15 to about 50%, from about 20 to about 50%, from about 25 to about 50%, from about 30 to about 50%, from about 35 to about 50%), from about 40 to about 50%, and from about 45 to about 50%).
  • the milk derivative is preferably selected from recombined, powdered or fresh skimmed milk, reconstituted whole or skimmed milk powder, skimmed milk concentrate, skim milk retentate, concentrated milk, ultraf ⁇ ltered milk retentate, milk protein concentrate (MPC), milk protein isolate (MPI), calcium depleted milk protein concentrate (MPC), low fat milk, low fat milk protein concentrate (MPC), casein, caseinate, milk fat, cream, butter, ghee, anhydrous milk fat (AMF), buttermilk, butter serum, beta serum, hard milk fat fractions, soft milk fat fractions, sphingolipid fractions, milk fat globule membrane fractions, phospholipid fractions, complex lipid fractions, colostrum, a colostrum fraction, colostrum protein concentrate (CPC), colostrum whey, an immunoglobulin fraction from colostrum, whey, whey protein isolate (WPI), whey protein concentrate (WPC), sweet whey, lactic acid w
  • the source of these derivatives may be milk or colostrum or a combination thereof.
  • the milk fat may be provided as fresh, recombined or powdered whole milk, one or more milk derivatives as described above, or combinations thereof.
  • the formulation may further comprise a suitable carrier.
  • the formulation may be formulated as a food, drink, food additive, drink additive, dietary supplement, nutritional product, medical food, enteral or parenteral feeding product, meal replacement, nutraceutical, medicament or pharmaceutical.
  • the formulation may be in the form of oil drops, a tablet, a caplet, a pill, a hard or soft capsule, a gummy or a lozenge.
  • the formulation may be in the form of a sachet, a dispensable powder, granules, a suspension, an elixir, a liquid, or any other form that can be added to food or drink, including for example water, milk or fruit juice.
  • the formulation may further comprise one or more constituents (such as antioxidants) which prevent or reduce degradation of the formulation during storage or after administration. These formulations may include any edible consumer product which is able to carry lipids.
  • suitable edible consumer products include aqueous products, baked goods, confectionary products including chocolate, gels, ice creams, reconstituted fruit products, snack bars, food bars, muesli bars, spreads, sauces, dips, dairy products including yoghurts and cheeses, drinks including dairy and non-dairy based drinks, milk, milk powders, sports supplements including dairy and non-dairy based sports supplements, fruit juice, food additives such as protein sprinkles and dietary supplement products including daily supplement tablets.
  • Suitable nutraceutical compositions useful herein may be provided in similar forms.
  • a further aspect of the invention provides a food ingredient, food product or dietary supplement comprising, consisting of or essentially consisting of MFGM and/or one or more of its components, or a formulation as described herein, for use in improving social- emotional behaviour and/or improving memory in an infant or child subject.
  • a formulation useful herein may be formulated as a food, drink, food additive, drink additive, dietary supplement, nutritional product, medical food, enteral or parenteral feeding product or meal replacement. Appropriate formulations may be prepared by an art skilled worker with regard to that skill and the teaching of this specification.
  • formulations useful herein include maternal formulas, infant formulas, follow-on formulas and growing up formulas, in liquid (concentrate or ready-to- drink) or powder form. Such products are formulated to target nutrients to the foetus, infant and child. It is appreciated by the first life-stages (foetus, infant and growing child) involve significant growth and development. Any support which enhances development can have significant effects on the development of the individual.
  • formulations useful herein include dietetic products.
  • the formulations useful herein may be formulated to allow for administration to a subject by any chosen route, including but not limited to oral administration. All percentages expressed herein are by weight of the composition on a dry matter basis unless specifically stated otherwise. The skilled artisan will appreciate that the term “dry matter basis” means that an ingredient's concentration or percentage in a composition is measured or determined after any free moisture in the composition has been removed.
  • dry matter basis means that an ingredient's concentration or percentage in a composition is measured or determined after any free moisture in the composition has been removed.
  • Figure 1 shows a flow chart of change in infant numbers in the MF (MFGM-enriched formula), SF (standard formula), and BFR (breast-fed reference) groups during the study period and reasons for dropping out of the study.
  • Figure 2 shows the composite attention and short-term memory scores, presented as mean ⁇ SE, in the MF group (white column), SF group (grey column), and BFR group (black column) at 6 and 12 months of age.
  • A Composite attention score among the three groups.
  • B Composite short-term memory score among the three groups: MF, SF and BFR.
  • Data were analysed using a general linear mixed model repeated measures with six time points adjusted for group and sex as fixed effects, group by sex interaction and site as a random effect with post hoc Bonferroni adjusted comparisons when the overall comparison was significant. To investigate potential different time trends within each group, the interaction between time and group were included in the model. *P ⁇ 0.05 (overall comparison).
  • EXAMPLES The following non-limiting examples are provided to illustrate the present invention.
  • the study population consisted of healthy full-term infants aged ⁇ 14 days who were born at the obstetric units and child healthcare units of four hospitals in the Fuzhou region, Fujian province, China, between January 2016 and October 2016.
  • the inclusion criteria were: (I) healthy newborn male and female infants regardless of mode of delivery (caesarean section or vaginal delivery); (II) gestational age between 37 and 41 weeks; (III) birth weight between 2500 and 4000 g; (IV) intention to predominantly breast feed (breast fed > 90%) or formula feed (formula fed > 60%) during the first 6 months after giving birth; (V) intention to remain in Fuzhou for approximately 15 ⁇ 18 months.
  • the exclusion criteria were: (I) 5-min Apgar score ⁇ 7; (II) obvious cerebral and/or other major birth defects or evidence of genetic disease at birth; (III) mothers who were not expected to comply with exclusive breastfeeding or formula feeding. Mothers who were intending to breastfeed or were breastfeeding were invited to take part in the study in the breastfed reference (BFR) group.
  • Supplemented formulae contained minimum ganglioside concentrations of 17.9 mg/100 g (infant formula) and 16.9 mg/100 g (follow-on formula) and were manufactured using a bovine MFGM-rich ingredient (SureStartTM MFGM Lipid 100; NZMP, Fonterra Co-operative Group Limited, New Zealand) as the source of complex milk lipids including gangliosides and phospholipids.
  • the control formula was manufactured with the same macro- and micronutrient composition but without fortification with the MFGM-rich ingredient (Table 1). Both infant formulae met standard nutritional requirements for infants from 0-6 months and 6-12 months(23). At each visit, parents/caregivers were asked to complete a 24-h recall of breastfeeding, formula feeding and intake of complementary foods.
  • the WHO Child Growth Standards were used to convert weight, length, and head circumference into weight-for- age, length-for-age, and head-circumference-for-age Z-scores (26; 27) .
  • the ganglioside species were separated on a Dionex UltiMate 3000 high performance liquid chromatography (HPLC) system (Thermo Scientific, MA, USA) equipped with an APS-2 Hypersil column (150 mm x 2.1 mm, particle size 3 ⁇ m; Thermo Electron Corporation, Waltham, MA, USA) (28) .
  • the sample injection volume was 10 ⁇ L.
  • the eluate from the HPLC system was introduced into a Q- Exactive Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Electron Corporation, Waltham, MA, USA) using a heated electrospray ionization source.
  • the ganglioside species were confirmed using the HPLC retention time and the precursor ion or the daughter ion of mass spectrum from six ganglioside standards during fragmentation.
  • the list of precursor and daughter ions was created by analyzing chromatograms of ganglioside standards and by referring to the literature (29) .
  • Total gangliosides were estimated as the sum of the measured major molecular species, i.e. GD1a, GD1b, GD3, GM1, GM2, and GM3.
  • the peak area for each ganglioside species was generated by the Thermo Xcalibur software using accurate mass extract. Quantification of each class of ganglioside was obtained by a specific linear equation generated from external standards.
  • GD1a (m/z 917 and 931), GD1b (m/z 917 and 931), GD3 (m/z 720 and 775), GM1 (m/z 1544), GM2 (m/z 1382), and GM3 (m/z 1151 and 1235) were used to quantify each class of ganglioside.
  • the molecular species used for the quantification covered all gangliosides found in all serum samples. g. Analysis of Blood Trace Elements The blood iron, zinc, magnesium, and calcium tests are a routine examination for 12 month-old infants in China according to “0 ⁇ 6 Years Old Children's Health Management Service Standards". These trace elements are essential for the growth and function of the brain(30).
  • Capillary blood (40 ⁇ L) was collected from the finger of infants. The samples were analyzed within 30 min using an automatic multi-element analyzer (Flame Atomic Absorption Spectrometry; BOHUI, H5300S, China). The concentrations of each trace element were calculated using a standard curve.
  • h Statistical Analysis Comparison of individual Bayley III outcomes (cognitive, motor, and verbal scores etc.), attention and short-term memory scores between MF and SF groups, and secondary pairwise comparisons between 3 groups were analysed using a general linear model with univariate analysis adjusted for socioeconomic factors (maternal age, parental education, and family income), with group and sex as fixed effects, group and sex interaction, and site as a random factor, following the published method (19).
  • ANOVA linear mixed model repeated measures analysis of variance
  • Gangliosides are important for the growth of neurons, synaptic connections, and memory formation (11; 39) .
  • High concentrations of gangliosides have been detected in both brain (40) and human breast milk (29) at different stages of lactation.
  • the most abundant types of ganglioside in human milk are GM3 and GD3, expressed early and late in lactation, (29) .
  • MFGM enrichment of infant formula may increase serum ganglioside concentrations to be more similar to that of the breast-fed infant, potentially supporting improved cognitive development (10; 21) .
  • Human breast milk is the optimal source of nutrition for the early stage of human life, as it provides all the necessary nutrients for normal growth and development.
  • MFGM-enriched formula in early life supports adequate growth and increases serum gangliosides levels, which may improve social emotional, general adaptive, and short- term memory measures of cognitive development in infancy using the validated Bayley- III assessment.
  • MFGM reduced the gap in cognitive development between breast-fed and formula-fed infants for all sub-scores of the Bayley-III test, suggesting that the MF group might resemble more closely the BFR group.
  • Table 1 International and micronutrient compositions of the infant and follow-on formulae enriched in MFGM (MF) and the control infant and follow-on formulae (SF).
  • Palmano K Rowan A, Guillermo R et al. (2015) The role of gangliosides in neurodevelopment. Nutrients 7, 3891-3913. 11. Mendez-Otero R, Pimentel-Coelho PM, Ukraintsev S et al. (2013) Role of Gangliosides in Neurological Development and the Influence of Dietary Sources. 12. Hussain G, Wang J, Rasul A et al. (2019) Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis 18, 26. 13. Zhang C, Susuki K, Zollinger DR et al.

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  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pediatric Medicine (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Dairy Products (AREA)

Abstract

La présente invention concerne l'utilisation de la membrane des globules gras du lait (MFGM) et/ou de ses composants pour améliorer les résultats du développement chez un nourrisson ou un sujet enfant, en particulier pour améliorer le comportement émotionnel social et améliorer la mémoire.
PCT/IB2022/054985 2021-05-28 2022-05-27 Complément alimentaire WO2022249136A1 (fr)

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EP22810773.6A EP4346449A1 (fr) 2021-05-28 2022-05-27 Complément alimentaire
CN202280052380.6A CN117794394A (zh) 2021-05-28 2022-05-27 食品补充剂

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EP21176741.3A EP4094591A1 (fr) 2021-05-28 2021-05-28 Complément alimentaire

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US20080292649A1 (en) * 2005-12-23 2008-11-27 N.V. Nutricia Composition for improving membrane composition and functioning of cells
US20110009349A1 (en) * 2007-10-19 2011-01-13 Fonterra Co-Operative Group Limited Methods of maintaining or increasing growth or cognitive development
US20140105875A1 (en) * 2011-06-08 2014-04-17 Nestec S.A. Nutritional compositions having exogenous milk fat globule membrane components
US20180360789A1 (en) * 2015-12-14 2018-12-20 Nestec S.A. Nutritional composition and infant formula for promoting myelination of the brain
WO2019215289A1 (fr) * 2018-05-09 2019-11-14 Mjn U.S. Holdings Llc Compositions nutritionnelles pédiatriques et procédés pour nourrissons nés par césarienne
WO2020188343A1 (fr) * 2019-03-21 2020-09-24 Fonterra Co-Operative Group Limited Compositions comprenant des lipides polaires pour maintenir ou augmenter la mobilité et la vitalité

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EP3079497B1 (fr) * 2013-12-12 2019-10-23 Société des Produits Nestlé S.A. Compositions de lait synthetique comprenant de l'acide eicosatrienoiquen-6 et des lipides polaires pour les nourrissons et enfants de moins de trois mois pour l'etablissement sain de la fonction cognitive

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US20080292649A1 (en) * 2005-12-23 2008-11-27 N.V. Nutricia Composition for improving membrane composition and functioning of cells
US20110009349A1 (en) * 2007-10-19 2011-01-13 Fonterra Co-Operative Group Limited Methods of maintaining or increasing growth or cognitive development
US20140105875A1 (en) * 2011-06-08 2014-04-17 Nestec S.A. Nutritional compositions having exogenous milk fat globule membrane components
US20180360789A1 (en) * 2015-12-14 2018-12-20 Nestec S.A. Nutritional composition and infant formula for promoting myelination of the brain
WO2019215289A1 (fr) * 2018-05-09 2019-11-14 Mjn U.S. Holdings Llc Compositions nutritionnelles pédiatriques et procédés pour nourrissons nés par césarienne
WO2020188343A1 (fr) * 2019-03-21 2020-09-24 Fonterra Co-Operative Group Limited Compositions comprenant des lipides polaires pour maintenir ou augmenter la mobilité et la vitalité

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Title
XIA YONG, JIANG BOWEN, ZHOU LIHONG, MA JUFEI, YANG LUYI, WANG FANGYUN, LIU HUIBING, ZHANG NAI, LI XIAOXIA, PETOCZ PETER, WANG BING: "Neurodevelopmental outcomes of healthy Chinese term infants fed infant formula enriched in bovine milk fat globule membrane for 12 months - A randomized controlled trial", ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION, vol. 30, no. 3, 1 September 2021 (2021-09-01), GB , pages 401 - 414, XP093013898, ISSN: 0964-7058, DOI: 10.6133/apjcn.202109_30(3).0007 *

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EP4094591A1 (fr) 2022-11-30
EP4346449A1 (fr) 2024-04-10
TW202313073A (zh) 2023-04-01
CN117794394A (zh) 2024-03-29
AU2022282664A1 (en) 2023-12-07

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